PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance. PD-1 is moderately expressed on naive T, B and NKT cells and up-regulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells (1).
Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), are expressed in human cancers arising in various tissues. In large sample sets of e.g. ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that PD-L1 expression correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment (2-13). Similarly, PD-1 expression on tumor infiltrating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma (14-15) and to correlate with poor prognosis in renal cancer (16). Thus, it has been proposed that PD-L1 expressing tumor cells interact with PD-1 expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.
Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 are in clinical development for treating cancer. It has been proposed that the efficacy of such antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune enhancing agents.
Disregulation of cell cycle control is a hallmark of all human cancers and is frequently associated with aberrant activation/regulation of cyclin-dependent kinases (CDKs). However, the CDK cascade is important for maintaining proper function of T cells in a context-dependent manner. Thus, the development of CDK inhibitors (CKDIs) as anti-cancer agents has been complicated by immune cell toxicities and the consequent potential for immunosuppressive effects (17). Dinaciclib, a pan-CDK inhibitor which selectively inhibits CDK1, CDK2, CDK5, and CDK9, has been investigated as a potential therapy in a variety of cancers, with neutropenia being the most common dose-limiting toxicity observed in clinical trials (17, 18).